There is an increasing interest in targeting soluble ligands as a compensation strategy for receptor-directed therapy of diseases mediated by ligand-receptor interactions. Insulin-like growth factors (IGFs), IGF-I and IGF-II, are circulating small soluble ligands (Ryan and Goss, 2008, Oncologist 13:16-24; Samani et al., 2007, Endocr Rev 28:20-47). They bind to the IGF receptor type I (IGF-IR) and activate multiple intracellular signaling pathways resulting in cell proliferation, survival, differentiation, and transformation. IGF-II also binds to insulin receptor (IR), primarily A isoform (IR-A), with high affinity. Many cells and tissues have hybrid receptors assembled with one chain of the IGF-IR and one of the IR. Elevated expression of the receptors and/or the ligands has been detected in some cancer tissues such as human breast carcinomas and linked to the pathogenesis of them.
Small-molecule tyrosine kinase inhibitors and mAbs against IGF-IR have shown benefits in human clinical trials (Ryan and Gross, supra). However, resistance to the IGF-IR-directed agents has developed (Hendrickson and Haluska, 2009, Curr Opin Investig Drugs 10:1032-40). A possible resistance mechanism is that cancer development and progression could rely solely on the actions taken by IR when the IGF-IR pathway is blocked. Thus, targeting both IR and IGF-IR may be necessary to completely inhibit the signal transductions. While IR is also functionally important for glucose homeostasis, targeting IGF-II is another strategy which could leave the insulin-IR interactions unaffected. Recently, several mAbs specific to IGF-II (or cross-reactive with IGF-I) have been identified that inhibit the growth and migration of human cancer cells in vitro and in vivo (Dransfield et al., 2010, Mol Cancer Ther 9:1809-19; Feng et al., 2006, Mol Cancer Ther 5:114-20; Gao et al., 2011, Cancer Res 71:1029-40; Goya et al., 2004, Cancer Res 64:6252-8; Kimura et al., 2010, Clin Cancer Res 16:121-9). However, a need remains for additional agents that target IGF-II and efficiently irreversibly remove it from the circulation.